chr1-216048620-T-C

Position:

chr1-216048620-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_206933.4(USH2A):c.6077A>G(p.Lys2026Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,614,122 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 7 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.324

Variant links:

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008856475).

BP6

Variant 1-216048620-T-C is Benign according to our data. Variant chr1-216048620-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216048620-T-C is described in Lovd as [Benign]. Variant chr1-216048620-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.6077A>G	p.Lys2026Arg	missense_variant	31/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.6077A>G	p.Lys2026Arg	missense_variant	31/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6077A>G	p.Lys2026Arg	missense_variant	31/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

613

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00108

AC:

271

AN:

251448

Hom.:

AF XY:

0.000765

AC XY:

104

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000438

AC:

640

AN:

1461822

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

272

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0161

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000927

GnomAD4 genome

AF:

0.00403

AC:

614

AN:

152300

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

293

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0142

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.000780

Hom.:

Bravo

AF:

0.00449

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00132

AC:

160

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 03, 2011

- -

Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.044

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0089

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.70

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.40

REVEL

Benign

0.081

Sift

Benign

0.69

Sift4G

Benign

0.24

Polyphen

0.0020

Vest4

0.18

MVP

0.85

MPC

0.028

ClinPred

0.0026

GERP RS

-0.39

Varity_R

0.042

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over